15-66703215-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_005585.5(SMAD6):c.-44C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,318,380 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 33)
  • Exomes 𝑓: 0.020 (314 hom.)
• Consequence: SMAD6 NM_005585.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

Genes affected

SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-66703215-C-T is Benign according to our data. Variant chr15-66703215-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1208555.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-66703215-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0148 (2255/152178) while in subpopulation NFE AF= 0.0227 (1541/67974). AF 95% confidence interval is 0.0217. There are 19 homozygotes in gnomad4. There are 1015 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.-44C>T		5_prime_UTR_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.980C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.980C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.-44C>T		5_prime_UTR_variant	1/4	1	NM_005585.5	P1
SMAD6	ENST00000612349.1	n.139C>T		non_coding_transcript_exon_variant	1/1
SMAD6	ENST00000557916.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2256 AN: 152070 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0159 AC: 541 AN: 34100 Hom.: 14 AF XY: 0.0150 AC XY: 275 AN XY: 18354

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00282

Gnomad FIN exome AF: 0.00731

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0203 AC: 23628 AN: 1166202 Hom.: 314 Cov.: 21 AF XY: 0.0197 AC XY: 11152 AN XY: 565456

Gnomad4 AFR exome AF: 0.00264

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.0000371

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00839

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0204

GnomAD4 genome AF: 0.0148 AC: 2255 AN: 152178 Hom.: 19 Cov.: 33 AF XY: 0.0136 AC XY: 1015 AN XY: 74412

Gnomad4 AFR AF: 0.00436

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0438

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00538

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0162 Hom.: 2

Bravo AF: 0.0153

Asia WGS AF: 0.00145 AC: 5 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138443554; hg19: chr15-66995553;